An NFATc1/SMAD3/cJUN Complex Restricted to SMAD4-Deficient Pancreatic Cancer Guides Rational Therapies.

Hasselluhn, Marie C; Schlösser, Denise; Versemann, Lennart; Schmidt, Geske E; Ulisse, Maria; Oschwald, Joana; Zhang, Zhe; Hamdan, Feda; Xiao, Harry; Kopp, Waltraut; Spitalieri, Jessica; Kellner, Christin; Schneider, Carolin; Reutlinger, Kristina; Nagarajan, Sankari; Steuber, Benjamin; Sastra, Stephen A; Palermo, Carmine F; Appelhans, Jennifer; Bohnenberger, Hanibal; Todorovic, Jovan; Kostyuchek, Irina; Ströbel, Philipp; Bockelmann, Aiko; König, Alexander; Ammer-Herrmenau, Christoph; Schmidleitner, Laura; Kaulfuß, Silke; Wollnik, Bernd; Hahn, Stephan A; Neesse, Albrecht; Singh, Shiv K; Bastians, Holger; Reichert, Maximilian; Sax, Ulrich; Olive, Kenneth P; Johnsen, Steven A; Schneider, Günter; Ellenrieder, Volker; Hessmann, Elisabeth

doi:10.1053/j.gastro.2023.10.026

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Title:: An NFATc1/SMAD3/cJUN Complex Restricted to SMAD4-Deficient Pancreatic Cancer Guides Rational Therapies.
Document type:: Article; Journal Article
Author(s):: Hasselluhn, Marie C; Schlösser, Denise; Versemann, Lennart; Schmidt, Geske E; Ulisse, Maria; Oschwald, Joana; Zhang, Zhe; Hamdan, Feda; Xiao, Harry; Kopp, Waltraut; Spitalieri, Jessica; Kellner, Christin; Schneider, Carolin; Reutlinger, Kristina; Nagarajan, Sankari; Steuber, Benjamin; Sastra, Stephen A; Palermo, Carmine F; Appelhans, Jennifer; Bohnenberger, Hanibal; Todorovic, Jovan; Kostyuchek, Irina; Ströbel, Philipp; Bockelmann, Aiko; König, Alexander; Ammer-Herrmenau, Christoph; Schmidleitner, Laura; Kaulfuß, Silke; Wollnik, Bernd; Hahn, Stephan A; Neesse, Albrecht; Singh, Shiv K; Bastians, Holger; Reichert, Maximilian; Sax, Ulrich; Olive, Kenneth P; Johnsen, Steven A; Schneider, Günter; Ellenrieder, Volker; Hessmann, Elisabeth «
Hasselluhn, Marie C; Schlösser, Denise; Versemann, Lennart; Schmidt, Geske E; Ulisse, Maria; Oschwald, Joana; Zhang, Zhe; Hamdan, Feda; Xiao, Harry; Kopp, Waltraut; Spitalieri, Jessica; Kellner, Christin; Schneider, Carolin; Reutlinger, Kristina; Nagarajan, Sankari; Steuber, Benjamin; Sastra, Stephen A; Palermo, Carmine F; Appelhans, Jennifer; Bohnenberger, Hanibal; Todorovic, Jovan; Kostyuchek, Irina; Ströbel, Philipp; Bockelmann, Aiko; König, Alexander; Ammer-Herrmenau, Christoph; Schmidleitne... »
Abstract:: BACKGROUND & AIMS: The highly heterogeneous cellular and molecular makeup of pancreatic ductal adenocarcinoma (PDAC) not only fosters exceptionally aggressive tumor biology, but contradicts the current concept of one-size-fits-all therapeutic strategies to combat PDAC. Therefore, we aimed to exploit the tumor biological implication and therapeutic vulnerabilities of a clinically relevant molecular PDAC subgroup characterized by SMAD4 deficiency and high expression of the nuclear factor of activated T cells (SMAD4-/-/NFATc1High). METHODS: Transcriptomic and clinical data were analyzed to determine the prognostic relevance of SMAD4-/-/NFATc1High cancers. In vitro and in vivo oncogenic transcription factor complex formation was studied by immunoprecipitation, proximity ligation assays, and validated cross model and species. The impact of SMAD4 status on therapeutically targeting canonical KRAS signaling was mechanistically deciphered and corroborated by genome-wide gene expression analysis and genetic perturbation experiments, respectively. Validation of a novel tailored therapeutic option was conducted in patient-derived organoids and cells and transgenic as well as orthotopic PDAC models. RESULTS: Our findings determined the tumor biology of an aggressive and chemotherapy-resistant SMAD4-/-/NFATc1High subgroup. Mechanistically, we identify SMAD4 deficiency as a molecular prerequisite for the formation of an oncogenic NFATc1/SMAD3/cJUN transcription factor complex, which drives the expression of RRM1/2. RRM1/2 replenishes nucleoside pools that directly compete with metabolized gemcitabine for DNA strand incorporation. Disassembly of the NFATc1/SMAD3/cJUN complex by mitogen-activated protein kinase signaling inhibition normalizes RRM1/2 expression and synergizes with gemcitabine treatment in vivo to reduce the proliferative index. CONCLUSIONS: Our results suggest that PDAC characterized by SMAD4 deficiency and oncogenic NFATc1/SMAD3/cJUN complex formation exposes sensitivity to a mitogen-activated protein kinase signaling inhibition and gemcitabine combination therapy.
Journal title abbreviation:: Gastroenterology
Year:: 2024
Journal volume:: 166
Journal issue:: 2
Pages contribution:: 298-312.e14
Fulltext / DOI:: doi:10.1053/j.gastro.2023.10.026
Pubmed ID:: http://view.ncbi.nlm.nih.gov/pubmed/37913894
Print-ISSN:: 0016-5085
TUM Institution:: Lehrstuhl für Translationale Tumorforschung (DKTK) (Prof. Saur)
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mediaTUM Gesamtbestand Einrichtungen Schools TUM School of Medicine and Health Departments Clinical Medicine Institut für Experimentelle Tumortherapie (Prof. Saur)Lehrstuhl für Translationale Tumorforschung (DKTK) (Prof. Saur)2024

mediaTUM Gesamtbestand Hochschulbibliographie 2024 Schools und Fakultäten TUM School of Medicine and Health Institut für Experimentelle Tumortherapie (Prof. Saur)